Cinchonine-derived catalysts and methods of using same

Abstract

The present invention includes certain conchinine-derived phase-transfer catalysts of formula (I), compositions comprising the same, and methods of promoting asymmetric addition reactions using the same.

What is claimed is: 
     
       1. A compound, or a salt, N-oxide, tautomer, enantiomer or diastereoisomer thereof, of formula (I): 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is 
 
       
         
           
           
               
               
           
         
         R 4  and R 5  are independently selected from the group consisting of alkyl, alkoxy and aryl 
         R 6  is selected from the group consisting of H, alkyl, alkoxy, aryloxy, —S(alkyl), —S(aryl), —OSiR 3  and —NR 2 ; and each occurrence of R is independently selected from alkyl and aryl; 
         R 2  is selected from the group consisting of optionally substituted alkyl, optionally substituted C 2 -C 6  alkenyl and optionally substituted C 2 -C 6  alkynyl, where each optional substituent is independently selected from the group consisting of alkyl, alkoxy, aryloxy, —S— alkyl, —S(aryl), —OSiR 3  and —NR 2 ; and 
         R 3  is selected from the group consisting of optionally substituted aryl and optionally substituted heteroaryl, where each optional substituent is independently selected from the group consisting of alkyl, alkoxy, chloro, phenyl, and acyl. 
       
     
     
       2. The compound of  claim 1 , wherein R 4  is aryl. 
     
     
       3. The compound of  claim 1 , wherein at least one selected from the group consisting of R 4  and R 5  is aryl, which is independently optionally substituted with at least one substituent selected from alkyl, alkoxy, —S(alkyl), and —OSiR 3 . 
     
     
       4. The compound of  claim 3 , wherein R 4  and R 5  are both independently aryl, each of which is independently optionally substituted with at least one substituent selected from alkyl, alkoxy, —S(alkyl), and —OSiR 3 . 
     
     
       5. The compound of  claim 1 , wherein R 6  is selected from the group consisting of alkyl, alkoxy, aryloxy, —S(alkyl), —S(aryl), —OSiR 3  and —NR 2 . 
     
     
       6. The compound of  claim 5 , wherein R 6  is selected from the group consisting of alkoxy and —OSiR 3 . 
     
     
       7. The compound of  claim 5 , wherein each occurrence of R is independently alkyl. 
     
     
       8. The compound of  claim 1 , wherein R 1  is selected from the group consisting of 3,5-dimethoxyphenyl, 3,5-diphenyl-phenyl, 3,5-(4-methoxyphenyl)-phenyl, 3,5-diphenyl-4-methoxy-phenyl and 3,5-diphenyl-4-(t-butyldimethylsiloxy)-phenyl. 
     
     
       9. The compound of  claim 1 , wherein R 2  is selected from the group consisting of unsubstituted alkyl, unsubstituted alkenyl and unsubstituted alkynyl. 
     
     
       10. The compound of  claim 9 , wherein R 2  is selected from the group consisting of unsubstituted alkyl and unsubstituted alkenyl. 
     
     
       11. The compound of  claim 10 , wherein R 2  is selected from the group consisting of vinyl and ethyl. 
     
     
       12. The compound of  claim 1 , wherein R 3  is selected from the group consisting of optionally substituted phenyl, optionally substituted pyrimidinyl, and optionally substituted phenanthryl. 
     
     
       13. The compound of  claim 12 , wherein R 3  is selected from the group consisting of 4-chloro-2,5-diphenyl-pyridin-6-yl and phenanthr-9-yl. 
     
     
       14. The compound of  claim 1 , which is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       (1S,2R,4S,5R)-2-((S)-((6-chloro-2,5-diphenylpyrimidin-4-yl)oxy)(quinolin-4-yl)methyl)-1-(3,5-dimethoxybenzyl)-5-vinylquinuclidin-1-ium (C-16); 
       
         
           
           
               
               
           
         
       
       (1S,2R,4S,5R)-1-([1,1′:3′,1″-terphenyl]-5′-ylmethyl)-2-((S)-((6-chloro-2,5-diphenylpyrimidin-4-yl)oxy)(quinolin-4-yl)methyl)-5-vinylquinuclidin-l-ium (C-18); 
       
         
           
           
               
               
           
         
       
       (1S,2R,4S,5R)-2-((S)-((6-chloro-2,5-diphenylpyrimidin-4-yl)oxy)(quinolin-4-yl)methyl)-1-((4,4″-dimethoxy-[1,1′:3′,1″-terphenyl]-5′-yl)methyl)-5-vinylquinuclidin-1-ium (C-20); 
       
         
           
           
               
               
           
         
       
       (1S,2R,4S,5R)-2-((S)-((6-chloro-2,5-diphenylpyrimidin-4-yl)oxy)(quinolin-4-yl)methyl)-1-((2′-methoxy-[1,1′:3′,1″-terphenyl]-5′-yl)methyl)-5-vinylquinuclidin-1-ium (C-21a); 
       
         
           
           
               
               
           
         
       
       (1S,2R,4S,5R)-1-((2′-((tert-butyldimethylsilyl)oxy)-[1,1′:3′,1″-terphenyl]-5′-yl)methyl)-2-((S)-((6-chloro-2,5-diphenylpyrimidin-4-yl)oxy)(quinolin-4-yl)methyl)-5-vinylquinuclidin-1-ium (C-21b); and 
       
         
           
           
               
               
           
         
       
       (1S,2R,4S,5R)-1-((2′-(tert-butoxy)-[1,1′:3′,1″-terphenyl]-5′-yl)methyl)-2-((S)-((6-chloro-2,5-diphenylpyrimidin-4-yl)oxy)(quinolin-4-yl)methyl)-5-vinylquinuclidin-1-ium (C-21c). 
     
     
       15. A method of promoting an asymmetric coupling reaction between an imine and a Michael acceptor substrate, the method comprising contacting the imine, the Michael acceptor substrate and at least one compound of any one of  claims 1 - 14 , wherein the imine comprises formula (II): 
       
         
           
           
               
               
           
         
       
       wherein:
 (a) R a  is trifluoromethyl, and R b  is selected from the group consisting of optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkenyl, and optionally substituted alkynyl, where each optional substituent is independently selected from the group consisting of alkyl, alkoxy, aryloxy, —S— alkyl, —S(aryl), —OSiR 3  and —NR 2 ; or 
 (b) R a  is H, and R b  is selected from the group consisting of optionally substituted aryl, optionally substituted heteroaryl, optionally substituted vinyl, and optionally substituted alkynyl; where each optional substituent is independently selected from the group consisting of alkyl, alkoxy, aryloxy, —S-alkyl, —S(aryl), —OSiR 3  and —NR 2 ; and 
 R c  is selected from the group consisting of optionally substituted alkyl, optionally substituted alkenyl, optionally substituted aryl, and optionally substituted heteroaryl, where each optional substituent is independently selected from the group consisting of alkyl, alkoxy, aryloxy, —S-alkyl, —S(aryl), —OSiR 3  and —NR 2 . 
 
     
     
       16. The method of  claim 15 , wherein the Michael acceptor substrate comprises at least one selected from the group consisting of an optionally substituted α,β-unsaturated aldehyde, an optionally substituted α,β-unsaturated ketone, an optionally substituted enone, an optionally substituted α,β-unsaturated carboxylic acid, an optionally substituted α,β-unsaturated carboxylic ester, an optionally substituted α,β-unsaturated amide, an optionally substituted α,β-unsaturated sulfone, and an optionally substituted α,β-unsaturated sulfoxide. 
     
     
       17. The method of  claim 16 , wherein a carbon-carbon bond is between carbon ‘1’ in (II) and the β-carbon in the Michael acceptor substrate. 
     
     
       18. The method of  claim 15 , wherein the at least one compound is selected from the group consisting of:
 (1S,2R,4 S, 5R)-2-((S)-((6-chloro-2, 5-diphenylpyrimidin-4-yl)oxy)(quinolin-4-yl)methyl)-1-(3,5-dimethoxybenzyl)-5-vinylquinuclidin-1-ium (C-16); 
 (1S,2R,4S,5R)-1-([1,1′:3′,1″-terphenyl]-5′-ylmethyl)-2-((S)-((6-chloro-2,5-diphenylpyrimidin-4-yl)oxy)(quinolin-4-yl)methyl)-5-vinylquinuclidin-1-ium (C-18); 
 (1S,2R,4S,5R)-2-((S)-((6-chloro-2,5-diphenylpyrimidin-4-yl)oxy)(quinolin-4-yl)methyl)-1-((4,4″-dimethoxy-[1,1′:3′,1″-terphenyl]-5′-yl)methyl)-5-vinylquinuclidin-1-ium (C-20); 
 (1S,2R,4S,5R)-2-((S)-((6-chloro-2,5-diphenylpyrimidin-4-yl)oxy)(quinolin-4-yl)methyl)-1-((2′-methoxy-[1,1′:3′,1″-terphenyl]-5′-yl)methyl)-5-vinylquinuclidin-1-ium (C-21a); 
 (1S,2R,4S,5R)-1-((2′-((tert-butyl dimethyl silyl)oxy)-[1,1′:3′,1″-terphenyl]-5′-yl)methyl)-2-((S)-((6-chloro-2,5-diphenylpyrimidin-4-yl)oxy)(quinolin-4-yl)methyl)-5-vinylquinuclidin-1-ium (C-21b); and 
 (1S,2R,4S,5R)-1-((2′-(tert-butoxy)-[1,1′:3′,1″-terphenyl]-5′-yl)methyl)-2-((S)-((6-chloro-2,5-diphenylpyrimidin-4-yl)oxy)(quinolin-4-yl)methyl)-5-vinylquinuclidin-1-ium (C-21c). 
 
     
     
       19. A method of isomerizing an imine of formula (II): 
       
         
           
           
               
               
           
         
       
       wherein:
 (a) R a  is trifluoromethyl, and R b  is selected from the group consisting of optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkenyl, and optionally substituted alkynyl, where each optional substituent is independently selected from the group consisting of alkyl, alkoxy, aryloxy, —S— alkyl, —S(aryl), —OSiR 3  and —NR 2 , or 
 (b) R a  is H, and R b  is selected from the group consisting of optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted vinyl, where each optional substituent is independently selected from the group consisting of alkyl, alkoxy, aryloxy, —S— alkyl, —S(aryl), —OSiR 3  and —NR 2 , and 
 R c  is selected from the group consisting of optionally substituted alkyl, optionally substituted alkenyl, optionally substituted aryl, and optionally substituted heteroaryl, where each optional substituent is independently selected from the group consisting of alkyl, alkoxy, aryloxy, —S-alkyl, —S(aryl), —OSiR 3  and —NR 2 ; the method comprising contacting the imine of formula (II) with at least one compound of any one of  claims 1 - 16 , thus forming a compound of formula (III): 
 
       
         
           
           
               
               
           
         
       
     
     
       20. The method of  claim 19 , wherein the at least one compound is selected from the group consisting of:
 (1S,2R,4S,5R)-2-((S)-((6-chloro-2,5-diphenylpyrimidin-4-yl)oxy)(quinolin-4-yl)methyl)-1-(3,5-dimethoxybenzyl)-5-vinylquinuclidin-1-ium (C-16); 
 (1S,2R,4S,5R)-1-([1,1′:3′,1″-terphenyl]-5′-ylmethyl)-2-((S)-((6-chloro-2,5-diphenylpyrimidin-4-yl)oxy)(quinolin-4-yl)methyl)-5-vinylquinuclidin-1-ium (C-18); 
 (1S,2R,4S,5R)-2-((S)-((6-chloro-2,5-diphenylpyrimidin-4-yl)oxy)(quinolin-4-yl)methyl)-1-((4,4″-dimethoxy-[1,1′:3′,1″-terphenyl]-5′-yl)methyl)-5-vinylquinuclidin-1-ium (C-20); 
 (1S,2R,4S,5R)-2-((S)-((6-chloro-2,5-diphenylpyrimidin-4-yl)oxy)(quinolin-4-yl)methyl)-1-((2′-methoxy-[1,1′:3′,1″-terphenyl]-5′-yl)methyl)-5-vinylquinuclidin-1-ium (C-21a); 
 (1S,2R,4S,5R)-1-((2′-((tert-butyldimethylsilyl)oxy)-[1,1′:3′,1″-terphenyl]-5′-yl)methyl)-2-((S)-((6-chloro-2,5-diphenylpyrimidin-4-yl)oxy)(quinolin-4-yl)methyl)-5-vinylquinuclidin-1-ium (C-21b); and 
 (1S,2R,4S,5R)-1-((2′-(tert-butoxy)-[1,1′:3′,1″-terphenyl]-5′-yl)methyl)-2-((S)-((6-chloro-2,5-diphenylpyrimidin-4-yl)oxy)(quinolin-4-yl)methyl)-5-vinylquinuclidin-1-ium (C-21c). 
 
     
     
       21. A kit comprising at least one compound of  claim 1 , and instructions for using the at least one compound to catalyze an asymmetric coupling reaction between an imine of formula (II) and a Michael acceptor substrate, and/or to catalyze the enantioselective or diastereoselective isomerization of an imine of formula (II): 
       
         
           
           
               
               
           
         
       
       wherein:
 (a) R a  is trifluoromethyl, and R b  is selected from the group consisting of optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkenyl, and optionally substituted alkynyl, where each optional substituent is independently selected from the group consisting of alkyl, alkoxy, aryloxy, —S— alkyl, —S(aryl), —OSiR 3  and —NR 2 ; or 
 (b) R a  is H, and R b  is selected from the group consisting of optionally substituted aryl, optionally substituted heteroaryl, optionally substituted vinyl, and optionally substituted alkynyl, where each optional substituent is independently selected from the group consisting of alkyl, alkoxy, aryloxy, —S-alkyl, —S(aryl), —OSiR 3  and —NR 2 ; and 
 R c  is selected from the group consisting of optionally substituted alkyl, optionally substituted alkenyl, optionally substituted aryl and optionally substituted heteroaryl, where each optional substituent is independently selected from the group consisting of alkyl, alkoxy, aryloxy, —S-alkyl, —S(aryl), —OSiR 3  and —NR 2 .